Dopamine is an important neurotransmitter in the central nervous system (CNS), as where it is involved with motor function, perception, arousal, motivation and emotion. Dopamine imbalance is believed to play a key role in a number of CNS-related disorders such as schizophrenia, Parkinson's disease, drug abuse, eating disorders and depression. Dopamine also has several important roles in the peripheral nervous system, such as in the control of blood to the kidneys and in autotonomic ganglion transmission.
Dopamine receptors in the CNS have traditionally been divided into two general categories, designated D-1 and D-2 receptors, based on biochemical and pharmacological differences between the two receptor types, and more recently from the study of the molecular biology of dopamine receptors in the CNS. (For a review of the classification and function of dopamine receptor subtypes, see C. Kaiser and T. Jain, “Dopamine Receptors: Functions, Subtypes and Emerging Concepts”, Medicinal Research Reviews, 5:145–229, 1985.) Recent additional evidence has suggested an even greater heterogeneity of the dopamine receptors with three additional dopamine receptors being defined through molecular cloning techniques: the D3 and D4, which are classified as D2-like, and the D5, which exhibits D1 receptor-like pharmacology (D. Sibley and F. Monsma, “Molecular Biology of Dopamine receptors”, in TIPS, Vol. 13, pp. 61–69, 1992). Attempts to understand the physiological and pathophysiological roles of the various dopamine receptors are continuing to unveil new avenues for novel therapeutic approaches for the treatment of dopamine-related disorders.
A particular dopamine-related problem involves the loss of striatal dopamine within the basal ganglia, the region of the mammalian brain that is involved with motor control, which has been established as the fundamental deficit in Parkinson's Disease and primary to the etiology of that disease state.
This deficiency is addressed via dopamine replacement therapy, primarily with L DOPA (3,4-dihydroxyphenylalanine), which is converted to dopamine within the brain. L-DOPA has been the cornerstone of Parkinson's Disease therapy, and the successes achieved with its therapy have led to the testing of other compounds capable of eliciting the post-synaptic receptor actions of dopamine.
Bromocriptine, the most widely used direct-acting dopamine agonist for the treatment of Parkinson's Disease, is administered adjunctively with L-DOPA in order to lower dosage of L-DOPA required to achieve the desired therapeutic response. Bromocriptine alone has been shown to relieve Parkinson's Disease symptoms in some patients, allowing for a delay in the onset of L-DOPA therapy, but the response to bromocriptine alone is not as great as that observed with L DOPA. The current therapies for Parkinson's Disease, including L-DOPA and bromocriptine, are, however, unfortunately associated with a number of serious side-effects and limitations, such as the development of dyskinesias, severe response fluctuations (on-off phenomenon) and diminishing efficacy during treatment.
An excess of dopamine in the brain, on the other hand, has bean identified, as a result of the pioneering work of Carlsson and others in the 1960's, as the cause of schizophrenia, a psychiatric illness involving disturbance of thought processes, hallucinations and loss of touch with reality. Chronic abuse of stimulants, such as amphetamines, known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is clinically indistinguishable from classic paranoid schizophrenia, further supporting this dopamine theory of schizophrenia.
Anti-schizophrenic drugs are postulated to exert their effects by blocking the dopamine receptors (i.e., acting as receptor antagonists), and consequently preventing excess receptor stimulation (G. P. Reynolds, “Developments in the drug treatment of schizophrenia”, in TIPS, :116–121, 1992). These antipsychotic agents frequently produce undesirable side-effects, however, the most common of which are the extrapyramidal effects that include bizarre involuntary movements and Parkinson-like states, as well as sedation and hypotension. Because of these often severe side-effects and the high incidence of patients unresponsive to dopamine blocking drugs, novel and improved therapies continue to be sought.
One such complement to dopamine receptor antagonists has included the use of low doses of dopamine agonists, such as apomorphine and bromocriptine. which have been reported to produce anti psychotic effects, possibly due to preferential activation of dopamine presynaptic receptors resulting in decreased dopaminergic activity (M. Del Zompo et al, “Dopamine agonists in the treatment of schizophrenia”, Progress in Brain Research, E:41–48, 1986 end H. Y. Meltzer, “Novel Approaches to the Pharmacology of Schizophrenia”, Drug Development Research, 9:23–40, 1986). In addition, the dopamine D1-selective agonist, SKF 38393, when used in conjunction with the antipsychotic drug, haloperidol, a D2 antagonist, has been shown to ameliorate the undesired side-effects of the haloperidol (M. Davidson, “Effects of the D-1 Agonist SKF-38393 Combined With Haloperidol in Schizophrenic Patients”, Arch Gen. Psychiatry, 42:190–191, 1990).
Growing evidence (reviewed by R. A. Wise and P. P. Rompre in “Brain Dopamine and Reward”, Annual Review of Psychology, 40:191–225, 1989) suggests that dopamine also has a central role in the brain's reward system. For example, animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist, presumably in order to maintain the elevated dopamine levels responsible for the drug's euphorigenic and reinforcing properties (D. R. Britten et al, “Evidence for Involvement of Both D1 and D2 Receptors in Maintaining Cocaine Self-Administration”, Pharmacology Biochemistry & Behavior, 89:911–915, 1991). The D-1 agonist, SKE 38393, has also been reported to decrease food intake by rats, presumably by direct action of the drug on neural feeding mechanisms. Because of this interrelationship between dopamine and reward, dopaminergic agents would be useful for the treatment of substance abuse and other addictive behavior disorders, including cocaine addiction, nicotine addiction and eating disorders.
Affective disorders, the most common psychiatric disorders in adults, which are characterized by changes in mood as the primary clinical manifestation, result from a reduction in the central nervous system of certain biogenic amine neurotransmitters, such as dopamine, noradrenaline and serotonin. Currently available antidepressants work primarily by raising biogenic amine neurotransmitter levels, by either inhibiting their uptake or preventing their metabolism. No antidepressant drug to date, however, can substitute for electroconvulsive shack therapy for the treatment of severe, suicidal depression.
Currently-available drugs for treating affective disorders, unfortunately, suffer from delayed onset of action, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the possibility of overdosing. A large number of clinically depressed individuals remain refractory to currently-available therapies.
A role for direct-acting dopamine agonists in antidepressant therapy has been suggested based on the effects observed for several dopamine agonists In various animal models (R. Muscat et al., “Antidepressant-like effects of dopamine agonists in an animal model of depression”, Biological Psychiatry, 31:937–946, 1992).
A role for dopamine has also been established in cognition and attention mechanisms. Animal studies support the role of dopamine in attention-related behaviors involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. Treatment of cognitive impairment and attention deficit disorders via dopamine-based therapy has been proposed and is under active investigation (F. Levy, “The Dopamine Theory of Attention Deficit Hyperactivity Disorder (ADHD)”, in Australian and New Zealand Journal of Psychiatry, 2:277–283, 1991).
In addition, dopamine has been identified with a number of effects in the periphery, and has been used in the treatment of shock, congestive heart failure and acute renal failure. Stimulation of the peripheral D-1 receptors causes vasodilation, particularly in the renal arid mesenteric vascular beds where large numbers of these receptors are found. The utility of dopamine has been limited, however, by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors, and by its emetic effects due to peripheral D-2 stimulation. Agents selective for the peripheral D-1 receptors appear to offer significant advantages over currently used treatments for these and other related disorders.
Also, dopamine in combination with diuretics has been reported to reverse radio-contrast media-induced acute renal failure in patients (Talley at al., Clin. Res., 18:518, 1970); thus suggesting that dopamine agonists may be similarly useful.
A wide variety of structures has been disclosed that are dopamine receptor ligands (H. E. Katerinopoulos and D. I. Schuster, “Structure-Activity Relationships for Dopamine Analogs A Review”, in Drugs Of The Future, Vol. 12, pp. 223–253, 1987) and include the thienopyridines, SKF 86926 (4-(3′,4′-dihydroxyphenyl) 4,5,6,7-tetrahydrotheno (2,3-c)-pyridine) and SKF 86915 (7-(3′,4′dihydroxyphenyl)-4,5,6,7-tetrahydrothlieno (3,2-c)-pyridine) (P. H. Andersen et al, European Journal of Pharmacology, 137:291–292, 1987, U.S. Pat. No. 4,340,600, to L. M. Brenner and J. R. Wardell, Jr., issued 1982, and U.S. Pat No. 4,282,227, to L. M. Brenner, issued 1981). Nichols at al. have disclosed certain substituted trans-hexahydrobenzo[a]-phenanthridine compounds as dopaminergic ligands (U.S. Pat. No. 5,047,536, to D. E. Nichols, issued 1991; W. K. Brewster al., “trans-10, 11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: A Highly Potent Selective Dopamine D1 Full Agonist”, in Journal of Medicinal Chemistry, D:1756-1784, 1990).
U.S. Pat. Nos. 5,047,536 and 6,194,423, incorporated herein, describe and claim the dopamine D1 agonists dihydrexidine (Formula I) and dinapsoline (Formula II) and their optionally substituted derivatives, respectively. PCT/US94/02894 describes the dopamine D-1 agonist A-86929 (Formula III), its diacylated derivated form (Formula IV) and other optionally substituted derivatives of A-86929. For the purpose of describing and specifying this invention, Formulas I–III shall be representative of dihydrexidine, dinapsoline, A-86929, respectively, and the various N- and C- substituted derivatives thereof described in the above-mentioned patent literature.

Each of the “parent” compounds (R1═R2═H) of Formulas I–III and their D-1 receptor agonist substituted derivatives/analogs share a common structural feature: adjacent phenolic hydroxy groups. The present invention is directed to monoester and asymmetrically substituted diester derivatives of such compounds and their receptor agonist substituted derivatives and analogs, where either one of the hydroxy groups is acylated with an ester-forming group or each of the adjacent phenolic hydroxy groups is acylated with a different ester-forming group. The compounds of the present invention exhibit unexpectedly improved pharmacokinetic properties, as compared to the previous described unacylated “parent” compounds.